期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 1, 页码 409-423出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01586
关键词
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资金
- U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC0206CH11357]
- Bill and Melinda Gates Foundation [OPP1066891]
- Wellcome Trust [100195/Z/12/Z]
- BMGF [OPP1024065, OPP1032548, OPP1126594, INV-009105, INV002178]
- NIAID-NIH (TB Structural Genomics grant) [P01A1095208]
- Welch foundation [A0015]
- Wellcome Trust [100195/Z/12/Z] Funding Source: Wellcome Trust
- Bill and Melinda Gates Foundation [OPP1032548, OPP1126594, OPP1066891] Funding Source: Bill and Melinda Gates Foundation
Although Benzofuran 1 showed promising activity against Mycobacterium tuberculosis as a potential lead for TB drugs, its inhibition of the hERG cardiac ion channel remained a significant challenge. Despite improvements in vitro, concerns arose when new compounds induced cardiac irregularities in ex vivo cardiotoxicity models, leading to the halt of further series development.
With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.
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